Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.

2nd Department of Paediatrics Semmelweis University Budapest 1094 Hungary

Canadian Centre for Computational Genomics McGill University Montreal QC H3A 0E9 Canada

Cancer Research Program The Research Institute of the McGill University Health Centre Montreal QC H4A 3J1 Canada; Division of Orthopedic Surgery Faculty of Surgery McGill University Montreal QC H3G 1A4 Canada

Children's Cancer Center The Royal Children's Hospital; and Murdoch Children's Research Institute; Parkville VIC 3052 Australia

Children's Cancer Center The Royal Children's Hospital; Murdoch Children's Research Institute; Department of Pediatrics University of Melbourne Parkville VIC 3052 Australia

Clinical Cooperation Unit Neuropathology German Cancer Consortium Heidelberg 69120 Germany

Dana Farber Boston Children's Cancer and Blood Disorders Center Boston MA 02215 USA

Dana Farber Boston Children's Cancer and Blood Disorders Center Boston MA 02215 USA; Department of Medical Oncology Dana Farber Cancer Institute Boston MA 02215 5450 USA; Department of Pediatrics Harvard Medical School Boston MA 02115 USA

Department of Biochemistry and Biophysics and Penn Epigenetics Institute Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104 6073 USA

Department of Biochemistry McGill University Montreal QC H3A 1A3 Canada

Department of Human Genetics McGill University Montreal QC H3A 0C7 Canada

Department of Human Genetics McGill University Montreal QC H3A 0C7 Canada; Division of Experimental Medicine Department of Medicine McGill University Montreal QC H4A 3J1 Canada; Department of Pediatrics McGill University and The Research Institute of the McGill University Health Centre Montreal QC H4A 3J1 Canada

Department of Human Genetics McGill University Montreal QC H3A 0C7 Canada; Lady Davis Research Institute Jewish General Hospital Montreal QC H3T 1E2 Canada

Department of Medical Oncology Dana Farber Cancer Institute Boston MA 02215 5450 USA; Broad Institute of MIT and Harvard Boston MA 02142 USA

Department of Medical Oncology Dana Farber Cancer Institute Boston MA 02215 5450 USA; Department of Pathology Boston Children's Hospital and Brigham and Women's Hospital Harvard Medical School and Department of Oncologic Pathology Dana Farber Cancer Institute Boston MA 02115 USA

Department of Neuropathology Institute of Pathology University Hospital Heidelberg Heidelberg 69120 Germany; Clinical Cooperation Unit Neuropathology German Cancer Consortium Heidelberg 69120 Germany

Department of Neurosurgery University of Debrecen Debrecen 4032 Hungary

Department of Neurosurgery University of Debrecen Debrecen 4032 Hungary; Department of Oncology Faculty of Medicine University of Debrecen Debrecen 4032 Hungary

Department of Oncology and The Milner Institute Jeffrey Cheah Biomedical Centre University of Cambridge Cambridge CB2 0AW UK

Department of Oncology and The Milner Institute Jeffrey Cheah Biomedical Centre University of Cambridge Cambridge CB2 0AW UK; CRUK Children's Brain Tumour Centre of Excellence University of Cambridge Cambridge CB2 0RE UK

Department of Oncology and The Milner Institute Jeffrey Cheah Biomedical Centre University of Cambridge Cambridge CB2 0AW UK; Nuclear Function in CNS Pathophysiology German Center for Neurodegenerative Diseases Bonn 53127 Germany

Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague 150 06 Czech Republic

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine Charles University and University Hospital Motol Prague 150 06 Czech Republic

Department of Pathology Centre Hospitalier Universitaire Sainte Justine Université de Montréal Montréal QC H3T 1C5 Canada

Department of Pathology Montreal Children's Hospital McGill University Health Centre Montreal QC H4A 3J1 Canada

Department of Pathology Montreal Neurological Institute McGill University Montreal QC H3A 2B4 Canada

Department of Pediatric Neurosurgery Centre Hospitalier Universitaire Sainte Justine Université de Montréal Montréal QC H3T 1C5 Canada

Department of Pediatric Oncology Dana Farber Boston Children's Cancer and Blood Disorders Center Boston MA 02215 USA

Department of Pediatrics Division of Hematology and Oncology Texas Children's Cancer and Hematology Centers Dan L Duncan Cancer Center Baylor College of Medicine Houston TX 77030 USA

Department of Pediatrics McGill University and The Research Institute of the McGill University Health Centre Montreal QC H4A 3J1 Canada

Developmental and Stem Cell Biology Program The Hospital for Sick Children Toronto ON M5G 0A4 Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children Toronto ON M5G 0A4 Canada

Division of Experimental Medicine Department of Medicine McGill University Montreal QC H4A 3J1 Canada

Division of Pediatric Hematology and Oncology University Medical Center Goettingen Goettingen 37075 Germany

Division of Pediatric Hematology and Oncology University Medical Center Goettingen Goettingen 37075 Germany; Pediatric Glioma Research Group German Cancer Research Center 69120 Heidelberg Germany

Hopp Children's Cancer Center Heidelberg Heidelberg 69120 Germany; Department of Pediatric Hematology and Oncology Heidelberg University Hospital Heidelberg 69120 Germany

Kids Cancer Centre Sydney Children's Hospital Randwick NSW 2031 Australia; School of Women's and Children's Health UNSW Sydney Kensington NSW 2052 Australia

Nuclear Function in CNS Pathophysiology German Center for Neurodegenerative Diseases Bonn 53127 Germany

Quantitative Life Sciences McGill University Montreal QC H3A 2A7 Canada; Lady Davis Research Institute Jewish General Hospital Montreal QC H3T 1E2 Canada

School of Computer Science McGill University Montreal QC H3A 2A7 Canada

UCL Queen Square Institute of Neurology London WC1N 3BG UK

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